Modern medical science is constantly searching for new and more powerful agents to prevent, treat, or retard infections and cure the diseases they cause. The cost of treating theses infections is astronomical, and can be in the range of billions of dollars every year. Vast sums of money are spent each year by pharmaceutical companies to identify, characterize, and produce new drugs. Reliable prophylactic treatments for disease prevention are also of major interest. Yet, despite the costs and the efforts to identify treatments for viral infections such as hepatitis, effective therapies remain elusive.
Hepatitis is a disease of the human liver. It is manifested with inflammation of the liver and is usually caused by viral infections and sometimes results from exposure to toxic agents. The hepatitis C virus (HCV) is spread through blood. It can infect people for long periods of time without causing obvious symptoms, but prolonged inflammation eventually damages the liver. Healthy liver cells are replaced by scar tissue that can keep the organ from functioning properly. Hepatitis may progress from fibrosis to liver cirrhosis, liver cancer, and eventually death. Death from the disease could triple over the next twenty years, as old infections reach clinical stages. Twenty percent of the carriers suffer acute viral hepatitis, 60-70% chronic hepatitis, and 30% cirrhosis, end-stage liver disease, and liver cancer (Chen, D. S. et al. (1996) Medical Assoc., 95(1):6-12).
Four millions Americans (about 1.8% of the USA population) have antibodies for HCV. Hepatitis C causes an estimated 8,000-12,000 deaths per year in the USA. The total deaths expected to be more than triple by the year 2010, which are about 38,000 per year, unless more effective treatments are found. World Health Organization (WHO) estimates that about 170 million people, 3% of the world's population are at risk of developing liver cirrhosis, and/or liver cancer. The prevalence of HCV-infection in some countries in Africa, the Eastern Mediterranean, South-East Asia and Western Pacific is high compared to some countries in North America and Europe. The following Table 1 shows Hepatitis C estimated prevalence and number infected by WHO Region.
TABLE 1Hepatitis C Prevalence and Number Infected by WHO RegionNumber ofcountriesby WHOTotalHepatitis CInfectedRegion whereWHOPopulationPrevalencePopulationdata areRegion(Millions)(Rate %)(Millions)not availableAfrica 6025.331.912Americas 7851.713.17Eastern 4664.621.37MediterraneanEurope 8581.038.919South-East Asia15002.1532.33Western Pacific16003.962.211Total58113.1169.757
Currently there is no effective cure or vaccine for HCV. Medications are available to slow down or stop the damage to the liver caused by HCV. The therapy for chronic hepatitis C has evolved steadily since alpha interferon was first approved for use in this disease more than 10 years ago. At the present time, the optimal regimen appears to be a 24- or 48-week course of the combination of pegylated alpha interferon and ribavirin. Treatment of HCV with interferon alone results in only about a 50% success rate. However, half of those responding relapse after cessation of interferon treatment. Therefore, only about 25% of the patients have a sustained response. It also gives rise to several side effects that cannot be tolerated by about 10% of the patients. Such side effects include severe flu symptoms. Many patients will consider stopping treatment because of these very troublesome symptoms, which include lethargy, hair loss, neuropsychiatric side effects, gastrointestinal symptoms, skin reactions, hormonal and metabolic symptoms, and undesirable tastes in the mouth. Some rare side effects can cause death from acute myocardial infarctions, strokes, suicides and sepsis.
Two forms of peginterferon have been developed and studied in large clinical trials: peginterferon alfa-2a (Pegasys: Hoffman La Roche: Nutley, N.J.) and peginterferon alfa-2b (Pegintron: Schering-Plough Corporation, Kenilworth, N.J.). These two products are roughly equivalent in efficacy and safety, but have different dosing regimens. Peginterferon alfa-2a is given subcutaneously in a fixed dose of 180 micrograms (mcg) per week. Peginterferon alfa-2b is given subcutaneously weekly in a weight-based dose of 1.5 mcg per kilogram per week (thus in the range of 75 to 150 mcg per week).
Ribavirin is an oral antiviral agent that has activity against a broad range of viruses. By itself, ribavirin has little effect on HCV, but adding it to interferon increases the sustained response rate by two- to three fold. For these reasons, combination therapy is now recommended for hepatitis C, and interferon monotherapy is applied only when there are specific reasons not to use ribavirin. Ribavirin is given twice a day in 200-mg capsules for a total daily dose based upon body weight. The standard dose of ribavirin is 1,000 mg for patients who weigh less than 75 kilograms (165 pounds) and 1,200 mg for those who weigh more than 75 kilograms. In certain situations, an 800-mg dose (400 mg twice daily) is recommended. Interferon acts against the virus via the immune system and does not reverse any physiological abnormalities or damage caused by the infection itself, e.g. hepatic cirrhosis.
In the United States three different regimens have been approved as therapy for hepatitis C: monotherapy with alpha interferon, combination therapy with alpha interferon and ribavirin, and pegylated interferon therapy. Interferon therapy costs $480/month ($5,760/year), Rebetron Combination therapy costs $1,560/month ($18,720/year), PEG-intron therapy costs $960-$1,114/month ($11,544-$13,368/year).
Prior to the availability of liver transplantation, the management of end-stage liver disease was limited to efforts to correct and control the complications associated with cirrhosis, and to comfort measures when all avenues had been exhausted. In the last decade, however, orthotopic liver transplantation has become an accepted treatment for patients with end-stage liver disease. However, management of the patient following transplantation has led to a wide variety of new challenges. The serious complications of end-stage liver disease and the decreased quality of life is the primary cause for the indication of liver transplantation. Clearly, patients with variceal bleeding, refractory ascites, hepatic encephalopathy, osteopenia, and malnutrition have a decreased quality of life due to the significant morbidity and potential mortality of each of these complications. In most cases, the indication for transplantation is easily recognized by the referring physician. The timing of referral for liver transplantation plays a crucial role in the management and survival of patients with end-stage liver disease. As the waiting lists and waiting times lengthen, the condition of the patient at the time of referral is of critical importance. Unfortunately, the number of patients dying on transplantation waiting lists is increasing (Todo, S. et al. (1991) Hepatology 13:619-626).
Table 2 summarizes transplantation data for the entire United States, including the number of candidates currently on the waiting list, by organ type. Included in this table are the totals for the number of transplants performed and donors recovered during the time periods specified.
TABLE 2Transplantation Data for the United StatesWaiting list candidates as of Mar. 25, 2003All80,639Kidney53,843Pancreas1,404Kidney/Pancreas2,403Liver16,957Intestine187Heart3,760Lung3,817Heart/Lung198*All candidates will be less than the sum due to candidates waiting formultiple organsTransplants performed January-December 2002Total25,765Deceased Donor19,160Living Donor6,605Donors recovered January-December 2002Total12,794Deceased Donor6,184Living Donor6,610*Based on OPTN data as of Mar. 21, 2003
Viral hepatitis has become a difficult problem for transplant centers before and after transplantation. Hepatitis B recurs in the transplanted liver in 80%-90% of patients. Hepatitis C is found in 20%-30% of patients at most transplant centers, and infection of the allograft occurs in 40%-45% of patients at one year post-transplant. These figures have led to the exclusion of hepatitis B patients from transplantation at many centers and careful consideration of patients with hepatitis C.
Post liver transplantation has led to a wide variety of new challenges; Infection of the allograft with hepatitis C leading to recurrent of disease, Cholestatic liver disease, Hepatocellular carcinoma, Biliary complications, Hyperlipidemia and Obesity, Graft-versus-Host Disease, and Chimerism (Liver Transplantation: The Hepatology Perspective by Jeffrey S. Crippin).
If the hepatitis virus could be eradicated prior to the time of transplantation, post-transplantation morbidity would likely be decreased. Unfortunately, therapeutic options are limited to interferon, an agent used with limited success in the non-transplant setting.
Immunological disorders have long been known as one of the serious health problems in the world. While the percentage of affected population and severity of the diseases are rising, current methods of treatment still primarily depend on empirical and serendipitous findings rather than from a scientific approach. At present, most patients are treated with drugs that aim at controlling symptoms resulted from the release of mediators by the effector cells. Although some drugs appear to be effective over a short-term and with few occurrence of adverse effects, long-term effects for preventing disease progression and permanent destruction are still largely unknown. For example, long-term oral therapy, such as steroid therapy, for treating asthma, is known to be associated with multiple debilitating effects such as growth delay, osteoporosis, and adrenal suppression. (Janeway, C. A. et al. (1994) Current Biology Ltd.).
Most of the marketed immunomodulators show non-reproducible and ambiguous results. Isolated or recombinant peptides and protein molecules (interferons, interleukins, antibodies, and vaccines) are very expensive and demonstrate many side effects and uncertain activities.
Immunomodulators offer a powerful tool for the control of host immunity by amplification or by suppression of the body's immune system. Stimulation of immunity is important in the host's defense against infectious diseases and cancer. Immunomodulators may activate macrophages that subsequently release mediators, including growth factors and cytokines. Immunomodulators may be used in the treatment of individuals with compromised immune system in order to enhance their immune response (Paul, W. E. (1989) Raven Press Ltd.). On the other hand, certain diseases may benefit from treatment with agents that down-regulate the immune system. For example, in patients suffering from autoimmune disorders, or in patients undergoing a transplant, it would be beneficial to treat with an agent that suppresses the immune response.
There is a great need to develop new immunomodulators which have significant immunomodulating activities, while at the same time exhibiting less toxicity, and which are readily accessible as compared to the marketed agents.